Aging and the Tissue Response to Misfolded Proteins

衰老和组织对错误折叠蛋白质的反应

• 批准号: 8054410
• 负责人: Joel N Buxbaum
• 金额: $ 36.97万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8054410
• 关键词: Affect; Age; Age of Onset; Aging; Alzheimer' s Disease; Amyloidosis; Animals; Apoptosis; Blood Circulation; Cardiac; Cells; Dependence; Deposition; Detection; Development; Disease; Event; Frequencies; Gender; Genes; Genetic Crosses; Genetic Transcription; Genomics; Heart; Hepatocyte; Human; Immune response; In Vitro; Inflammation; Kidney; Kinetics; Label; Liver; Measures; Molecular; Molecular Chaperones; Mutation; Natural Immunity; Non-Insulin-Dependent Diabetes Mellitus; Organ; Organism; Oxidants; Pattern; Phenotype; Play; Prealbumin; Process; Protein Conformation; Protein Precursors; Proteins; Proteomics; Radioactive; Relative (related person); Role; SOD2 gene; Series; Techniques; Tissues; Transgenic Animals; Transgenic Model; animal tissue; base; islet amyloid polypeptide; oxidant stress; protein misfolding; response

DESCRIPTION (provided by applicant): Disorders of protein conformation of wild type proteins increase in frequency with aging. Alzheimers Disease, type II diabetes and senile systemic amyloidosis are the result of tissue deposition of the wild type protein precursors A2, islet amyloid polypeptide and transthyretin, respectively. In the case of A2 and the islet amyloid polypeptide, aggregation and deposition take occur in proximity to the cells producing the precursor proteins. In senile systemic amyloidosis, transthyretin is synthesized in the liver but deposits in the heart, gut and carpal tunnel, never the liver. Biophysical analyses of the processes of aggregation and fibril formation in vitro show similar kinetics for all three proteins, although transthyretin aggregation differs from the others in that it cannot be seeded. We have produced a transgenic model of senile systemic amyloidosis that resembles human senile systemic amyloidosis in terms of its target tissues (heart, gut, kidneys, but not liver), age of onset (from over one year to 2.5 years, and tissue deposition (non-fibrillar and fibrillar). In our analysis of the tissues of these animals, we have found that animals with significant cardiac deposition have a significantly different transcription pattern in both liver and heart than age and gender matched transgenic animals that do not display significant cardiac transthyretin deposition. We have hypothesized that the transcriptional response of the liver to presumably misfolded transthyretin plays a role in tissue deposition at a distance, i.e. in the heart. If the response is not qualitatively or quantitatively sufficient, partially misfolded transthyretin is released from the hepatocyte into the circulation and is free to aggregate and deposit in the heart and kidneys. We will use genomic and proteomic analyses and genetic crosses to investigate the molecular events in the liver, the state of circulating transthyretin, transcription patterns in the target tissues in the transgenic animals and how these vary with aging, genetically induced reduced responsiveness to oxidant stress, genetically determined chaperone deficiency, and a genetic defect in the innate immune response. At the completion of these studies, we should have a more complete understanding of the way in which intact higher organisms respond to potentially pathogenic misfolded proteins and how these processes are affected in aging.

描述（申请人提供）：野生型蛋白构象紊乱随年龄增长而增加。阿尔茨海默病、II型糖尿病和老年性全身性淀粉样变性分别是野生型蛋白前体A2、胰岛淀粉样多肽和转甲状腺素组织沉积的结果。在A2和胰岛淀粉样多肽的情况下，聚集和沉积发生在产生前体蛋白的细胞附近。在老年性系统性淀粉样变性中，转甲状腺素在肝脏合成，但沉积在心脏、肠道和腕管，而不是肝脏。体外聚集和纤维形成过程的生物物理分析表明，这三种蛋白质的动力学相似，尽管转甲状腺素聚集与其他蛋白质的不同之处在于它不能被播种。我们已经建立了一种老年性系统性淀粉样变性的转基因模型，其靶组织（心脏、肠道、肾脏，但不包括肝脏）、发病年龄（从1岁以上到2.5岁）和组织沉积（非原纤维和原纤维）方面与人类老年性系统性淀粉样变性相似。在我们对这些动物组织的分析中，我们发现有明显心脏沉积的动物在肝脏和心脏的转录模式明显不同于年龄和性别匹配的转基因动物，没有明显的心脏转甲状腺素沉积。我们假设肝脏对可能错误折叠的转甲状腺素的转录反应在远处（即心脏）的组织沉积中起作用。如果反应在质量或数量上不充分，部分错误折叠的甲状腺素从肝细胞释放到循环中，自由聚集并沉积在心脏和肾脏中。我们将使用基因组学和蛋白质组学分析以及遗传杂交来研究肝脏中的分子事件、循环转甲状腺素的状态、转基因动物靶组织中的转录模式以及这些如何随着衰老、基因诱导的氧化应激反应降低、基因决定的伴侣蛋白缺乏和先天免疫反应中的遗传缺陷而变化。在完成这些研究后，我们应该对完整的高等生物体对潜在致病性错误折叠蛋白的反应方式以及这些过程如何在衰老中受到影响有更全面的了解。